title: Combination of genetic and quantitative serological immune markers are associated with complicated Crohn's disease behavior.
abstract: BACKGROUND
  Treatment of Crohn's disease (CD) with biologics may alter disease progression, leading to fewer disease-related complications, but cost and adverse event profiles often limit their effective use. Tools identifying patients at high risk of complications, who would benefit the most from biologics, would be valuable. Previous studies suggest that biomarkers may aid in determining the course of CD. We aimed to determine if combined serologic immune responses and NOD2 genetic markers are associated with CD complications.
  
  
  METHODS
  In this cross-sectional study, banked blood from well-characterized CD patients (n = 593; mean follow-up: 12 years) from tertiary and community centers was analyzed for six serological biomarkers (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-I2, pANCA). In a patient subset (n = 385), NOD2 (SNP8, SNP12, SNP13) genotyping was performed. Complications included stricturing and penetrating disease behaviors. A logistic regression model for the risk of complications over time was constructed and evaluated by cross-validation.
  
  
  RESULTS
  For each serologic marker, complication rates were stratified by quartile. Complication frequency was significantly different across quartiles for each marker (P trend ≤ 0.001). Patients with SNP13 NOD2 risk alleles experienced increased complications versus patients without NOD2 mutations (P ≤ 0.001). A calibration plot of modeled versus observed complication rates demonstrated good agreement (R = 0.973). Performance of the model integrating serologic and genetic markers was demonstrated by area under the receiver operating characteristic curve (AUC = 0.801; 95% confidence interval: 0.757-0.846).
  
  
  CONCLUSIONS
  This model combining serologic and NOD2 genetic markers may provide physicians with a tool to assess the probability of patients developing a complication over the course of CD.
authors.affiliation: Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Gary.Lichtenstein@uphs.upenn.edu
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lichtenstein
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Marla C
authors.initials: MC
authors.lastname: Dubinsky
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Derren M
authors.initials: DM
authors.lastname: Barken
authors.forename: Fred
authors.initials: F
authors.lastname: Princen
authors.forename: Susan
authors.initials: S
authors.lastname: Carroll
authors.forename: Michelle
authors.initials: M
authors.lastname: Brown
authors.forename: Jordan
authors.initials: J
authors.lastname: Stachelski
authors.forename: Emil
authors.initials: E
authors.lastname: Chuang
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Landers
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Stempak
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D003251:Constriction, Pathologic / Q000097:blood / Q000175:diagnosis* / Q000209:etiology*; D003424:Crohn Disease / Q000097:blood / Q000150:complications* / Q000235:genetics; D003430:Cross-Sectional Studies; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein